We recently measured cerebrospinal fluid (CSF) neuroactive steroids that modulate inhibitory gamma-amino- butyric acid (GABA)A and excitatory N-methyl-D-aspartate (NMDA) receptor function in premeno-pausal women with chronic PTSD using gas chromatography, mass spectrometry (GC-MS). Two of these steroids, 3a-hydroxy-5a-pregnan-20-one (allopregnanolone) and its equipotent stereoisomer, 3a-hydroxy-5b-pregnan- 20-one (pregnanolone), collectively termed ALLO, are the most potent and selective positive endogenous modulators of GABA action at brain GABAA receptors and demonstrate potent anxiolytic, sedative, anesthetic and neuroprotective effects. We also measured the precursors for ALLO: progesterone (PROG) and 5a- dihydroprogesterone (5a-DHP), as well as dehydroepiandrosterone (DHEA), a steroid that antagonizes and positively modulates, respectively, GABAA and NMDA receptor function. Levels of CSF PROG, 5a-DHP, and DHEA did not differ significantly between the PTSD and healthy subjects. PTSD ALLO levels were, however, low at just ~39% of healthy subject levels. In addition, the ALLO/DHEA ratio correlated strongly and negatively with depression and PTSD re-experiencing symptoms, suggesting that a reduction in inhibitory neurotransmission due to low ALLO levels influences the severity and comorbid features of PTSD. While intriguing, the small sample size, potential confounding effects of age and oral contraceptive use, and restriction of the sample to women with follicular phase PROG levels limit the generalizability of the findings. The purpose of this R21 proposal is thus to measure CSF levels of PROG, 5a-DHP, ALLO, and DHEA, as well as DHEAS, testosterone, cortisol and GABA in men with and without PTSD, and in women during the natural follicular and mid-luteal menstrual phases using a "within subjects" design. In the larger samples proposed, we can more reliably examine relationships between these steroids and patterns of PTSD and depressive symptoms. We also will examine whether transcranial magnetic stimulation (TMS) measures of cortical inhibition correlate with GABAergic neuroactive steroid and GABA measures. PTSD affects ~8% of the general population and 15-20% of persons exposed to sexual assault, compound community trauma, and combat; women are affected at twice the rate of men. The goal of this research is to identify new neurobiological targets to guide development of improved methods for PTSD treatment and prevention. [unreadable] [unreadable] [unreadable]